The glucose concentration in blood is of fundamental importance for human and animal metabolism. The following is limited to the ratios in humans but also apply in principle to numerous animals. Glucose is a central provider of energy to almost all areas of the human body. In healthy humans the glucose concentration in the blood is effectively regulated. The glucose concentration in the blood, also called blood sugar level, increases in particular after the consumption of carbohydrate-containing food. In order to counteract this, more of the hormone insulin is spilled out into the blood from the islet cells of the abdominal salivary gland. The insulin reduces the blood sugar level by transporting the glucose from the blood plasma and from the tissue liquid into the interior of the cell. If, on the other hand, the blood sugar level is too low, then principally the hormone glucagon becomes active. This regulating circle keeps the glucose concentration in the blood of healthy humans in the range of from 80-100 mg/dl (this corresponds to 4.4-6.7 mmol/l).
If there is any disruption to this regulating circle, for example due to insulin insufficiency or resistance to insulin, the glucose concentration experiences much greater fluctuations, and the symptoms of diabetes mellitus present themselves. A distinction is drawn between two diabetes types. In type 1 there is a disturbance of the islet cells in the abdominal salivary gland, with the result that in its advanced stage, no more insulin can actually be produced by the body. The islet cells are at least partly still intact in type 2, but other malfunctions, such as insulin resistance, hyperinsulinism, relative insulin insufficiency or dysendocrinisms are present. In type 1, in every case, a regular dose of externally administered insulin is required. In type 2, previously also called adult-onset diabetes, there are also various other medicaments for treatment.
According to figures from the WHO, there are approx. 8 million diabetics in Germany alone, with an estimated worldwide figure of 300 million by the year 2025. Above all in industrialized nations, the relative proportion of diabetics in the population has also been increasing clearly for years.
If diabetes is not treated, in the event of chronic hyperglycaemia a patient can suffer massive damage to eyes, organs and limbs. While hypoglycaemia can easily be recognized by patients themselves who know about their illness thanks to various symptoms and compensated for by taking dextrose, the position is different with hyperglycaemia. Too high a blood sugar level is barely detectable by those affected.
In both diabetes types the blood sugar level must therefore be measured at regular intervals in order to be able to ascertain the optimum dose of insulin or other medicaments. In extreme cases the glucose concentration in the blood can increase to up to 1000 mg/dl, which corresponds to approximately ten times the normal concentration. Relatively frequently, concentrations of up to 300 mg/dl occur, in particular after consuming too many carbohydrates. The absolute standard for measuring the blood sugar level by the doctor or the patient himself is currently the use of so-called blood sugar measurement strips. Their use requires blood to be taken from the diabetic. If no blood sample is already available, the diabetic generally pricks a fingertip with a special needle in order to obtain a drop of blood. The drop of blood is placed on the blood sugar measurement strips. An enzymatic reaction takes place, after which the glucose concentration can be determined via an electrical measurement. The glucose concentration is required to be ascertained with an error of at most 15%. Depending on the phase of the illness and markedness the measurement must be repeated up to seven times a day.
The disadvantages of this invasive measurement method are obvious: 1. Pricking the fingertip is extremely painful. 2. Skin impurities can lead to measurement errors. 3. There is an increased risk of infection due to the frequent damaging of the skin. Additionally, the blood sugar measurement strips have limited storability. The high number of non-reusable blood sugar measurement strips results in enormous costs for health insurers and patients.
It is known that the glucose concentration in the aqueous humour accounts for approximately 70% of the glucose concentration in the blood, wherein the temporal concentration pattern in the blood is some minutes ahead of the aqueous humour. The glucose in the aqueous humour serves above all to supply energy to the cornea and the lens of the eye, as these two constituents of the eye must not contain any blood vessels, for optical reasons. In order to avoid the mentioned disadvantages of the blood sugar measurement strips it can be attempted to measure the glucose concentration in the blood indirectly via the glucose concentration in the aqueous humour. The aqueous humour is a clear liquid in the anterior and posterior chambers of the eye. Only the anterior chamber, which is located between cornea and lens of the eye, is sufficiently accessible. Because of the blood-aqueous humour barrier, the aqueous humour contains a type of ultrafiltrate of the blood. In other words, nearly all cell constituents and proteins are filtered out, with the result that only water, dissolved salts and small dissolved molecules still enter the aqueous humour. The dissolved substances in the aqueous humour include i.a. NaCl, glucose, lactate, ascorbic acid, amino acids and urea.
In principle, essentially the following optical methods are conceivable for measuring the glucose concentration in the aqueous humour: interferometry, confocal measurements, polarimetry, reflectometry, measurement of Raman scattering and absorption measurements in the infrared range. There are already publications relating to each of the methods. Thus far, however, a sufficient precision and reliability when determining the glucose in the aqueous humour has yet to be achieved with any of the methods. As the glucose generally dominates the optical activity in the aqueous humour, polarimetry is a priori a relatively specific method, i.e. there is a good correlation between optical activity and glucose concentration. It is this which basically distinguishes polarimetry from most other optical methods. Interferometric methods react for example very sensitively to the relatively strongly fluctuating salt content of the aqueous humour. As salts do not display any optical activity at all, polarimetry is completely insensitive to fluctuations in salt concentration. The present invention can be considered to use polarimetry, therefore the further description of the state of the art will concentrate on this method.
An array is described in U.S. Pat. No. 3,963,019A1 in which a light beam strikes the iris of the eye and the light reflected or scattered by the iris is detected with an optical analyzer. In one embodiment the light beam is polarized, and a second polarizer is located in front of the optical analyzer. The measurement array is calibrated using a known glucose concentration. It is proposed to measure the blood sugar level with this array. For the following reasons it can, however, be assumed that this is not possible with the described array. With an assumed glucose concentration of 100 mg/dl, the rotation of the polarization plane through the glucose is only approximately 0.005 degrees. Because of the medically necessary relative precision of 15% when determining the concentration, a rotation of 0.00075 degrees must be triggered. In order to be able to measure such small changes there must be a relative intensity resolution of better than 1E-4. However, light sources generally have temporal drifts or fluctuations in the radiated intensity which lie at least in the permil range, but frequently even in the percent range. This applies both to incandescent lamps and arc lamps and to light-emitting diodes and lasers. Moreover, the eye carries out saccades and microsaccades, i.e. involuntary movements. The region of the iris which the light beam strikes thereby fluctuates. As the iris has reflection and scatter characteristics which display pronounced spatial variations, the result is an additional considerable fluctuation in intensity at the optical analyzer. The expected fluctuations in intensity due to the light source and the saccades prevent the much smaller variations in intensity due to the polarization rotation from being able to be measured with the described array.
A device is described in document DE4243142A1 which is very similar to that in U.S. Pat. No. 3,963,019A1, but also has a Faraday modulator with which the input polarization can be periodically varied. In combination with a lock-in amplifier, the Faraday modulator is intended to improve detection. However, left completely out of account is the fact that the measurement radiation must pierce the extremely birefringent cornea twice. It can be assumed that the birefringence of the cornea influences the polarization of the measurement-radiation light at least a thousand times more strongly than the glucose in the aqueous humour. The degree of the corneal birefringence depends greatly on the polarization direction in which the cornea is irradiated. By using the Faraday modulator, mainly a varying birefringence is induced which is much greater than the change in polarization of the glucose. The same problems as have already been named with regard to U.S. Pat. No. 3,963,019A1 also occur.
U.S. Pat. No. 6,704,588B2 proposes a method in which the lens of the eye is irradiated exactly at Brewster's angle, in order to create pure s-polarization when the radiation is reflected by the lens of the eye. However, it must be assumed that this approach is insufficient to compensate for the influence of the saccades and microsaccades. The problem is that the eye movements cause not only variations in the birefringence but also variations in the angle of incidence at the lens of the eye. Even if the angle variations are only fractions of a degree, the changes in polarization due to the fluctuating angle of incidence and the fluctuating birefringence are much greater than the polarization influence due to the glucose in the aqueous humour. As these effects cannot be separated on detection side, it appears unrealistic that physiological glucose concentrations in the aqueous humour can be measured with the method.
A device is described in DE102005020912A1 in which a polarization-rotating element, such as e.g. a lambda/2 plate, is used. The aim is to poll the polarization-changing action of the whole eye for as many different input polarizations as possible of the measurement radiation. Here, too, the problem is that on detection side it can no longer be distinguished whether or to what extent a certain change in polarization has been caused by the glucose, the birefringence of the cornea or the reflection at the lens of the eye.
DE102005020911A1 proposes a measurement concept in which, using Faraday modulators, at least two different polarizations of the input radiation are produced, in order firstly to produce a defined polarization state at the lens of the eye. Starting from this initial condition at the lens of the eye it is expected that subsequently only the polarization rotation of the glucose and the birefringence of the second corneal passage still change the polarization. Because the glucose causes only a rotation of the polarization plane, but the corneal passage a phase shift between s- and p polarization, there is the chance that the influence of the glucose can be measured via the rotation of the resulting polarization ellipse after the measurement radiation leaves the eye. However, the device is very costly and requires the use of Faraday modulators which are expensive and difficult to operate.